Nitric oxide down-regulates voltage-gated Na+ channel in cardiomyocytes possibly through S-nitrosylation-mediated signaling

• Main Authors: Pu Wang, Mengyan Wei, Xiufang Zhu, Yangong Liu, Kenshi Yoshimura, Mingqi Zheng, Gang Liu, Shinichiro Kume, Masaki Morishima, Tatsuki Kurokawa, Katsushige Ono
• Format: Article
• Language: English
• Published: Nature Publishing Group 2021-05-01
• Series: Scientific Reports
• Online Access: https://doi.org/10.1038/s41598-021-90840-0

Abstract Nitric oxide (NO) is produced from endothelial cells and cardiomyocytes composing the myocardium and benefits cardiac function through both vascular-dependent and—independent effects. This study was purposed to investigate the possible adverse effect of NO focusing on the voltage-gated Na+ channel in cardiomyocytes. We carried out patch-clamp experiments on rat neonatal cardiomyocytes demonstrating that NOC-18, an NO donor, significantly reduced Na+ channel current in a dose-dependent manner by a long-term application for 24 h, accompanied by a reduction of Nav1.5-mRNA and the protein, and an increase of a transcription factor forkhead box protein O1 (FOXO1) in the nucleus. The effect of NOC-18 on the Na+ channel was blocked by an inhibitor of thiol oxidation N-ethylmaleimide, a disulfide reducing agent disulfide 1,4-Dithioerythritol, or a FOXO1 activator paclitaxel, suggesting that NO is a negative regulator of the voltage-gated Na+ channel through thiols in regulatory protein(s) for the channel transcription.